Researchers at McGill University’s Faculty of Medicine have identified an unexpected function of a family of proteins referred to as “molecular chaperones” that are known to protect cells against environmental stresses such as heat. Their findings were reported recently in Nature Communications.
“Our study shows for the first time that these chaperones can reshape the injured architecture of a mutant protein molecule toward its normal structure, both at the cell surface and in a test tube,” explains Dr. Gergely Lukacs, Professor and Canada Research Chair in the Departments of Physiology and Biochemistry at McGill. “The results represent a novel role for these proteins which may be exploited in the future to modulate the severity of diseases.”
The team was primarily interested in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Since CFTR transports ion and water across the cells that line the airways and other organs, its malfunction, which is caused by a large number of genetic mutations, leads to severe lung infections, a hallmark of the cystic fibrosis (CF) disease. “The underlying molecular cause is that the most common mutations impose structural stresses or damages on CFTR architecture and it becomes largely, but not completely, trapped inside cells instead of accumulating at the cell surface,” notes Miklos Bagdany, a research associate in Dr. Lukacs’ lab and the study’s first author.
The small amount of CFTR that accumulates at the cell surface, whether spontaneously or following drug treatment, is recognized by the body as structurally misbehaved and is rapidly targeted for degradation. “Since chaperones facilitate the maturation of newly-made healthy CFTR architecture inside the cells, we asked whether they can limit or reverse the structural defects of mutants at the cell surface, similar to a plastic cast that stabilizes a broken bone against dislocation,” says Dr. Lukacs. “This was indeed the case. Chaperones shift the mutant CFTR architecture towards its normal form, which results in increased function and stability of the mutant channel. This was demonstrated at the surface of lung cells, as well as by measuring the tiny current that flows through a single CFTR molecule.”
This discovery has many potential impacts. Depending on their activity, the chaperones may change the severity of CF disease in individual patients, contributing to highly variable manifestation of the diseases with the same mutations. Future research may identify small molecule therapeutics that can activate chaperone systems, to replicate what this initial study shows in cells, in order to alleviate CF symptoms by increasing the mutant channel function at the cell surface.
This study was conducted in collaboration with Dr. Jason Young of the Department of Biochemistry at McGill, Dr. William Balch from The Scripps Research Institute in the United States and Giorgio Colombo from the Istituto di Chimica del Riconoscimento Molecolare in Italy.
Funding was provided through grants from the Canadian Institutes of Health Research, the National Institutes of Health, Cystic Fibrosis Canada, Cystic Fibrosis Foundation Therapeutics, the Canada Foundation for Innovation, and the Canada Research Chairs program.
The article, “Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell” was published in Nature Communications on August 30, 2017.
September 13, 2017